CN102762569B - Benzodiazepine bromodomain inhibitor - Google Patents

Benzodiazepine bromodomain inhibitor Download PDF

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Publication number
CN102762569B
CN102762569B CN201080050285.XA CN201080050285A CN102762569B CN 102762569 B CN102762569 B CN 102762569B CN 201080050285 A CN201080050285 A CN 201080050285A CN 102762569 B CN102762569 B CN 102762569B
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compound
formula
acceptable salt
phenyl
pharmacy acceptable
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CN102762569A (en
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R·L·M·戈斯米尼
O·米尔盖
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GlaxoSmithKline China Investment Co Ltd
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Priority claimed from GB0919433A external-priority patent/GB0919433D0/en
Priority claimed from GBGB1010509.6A external-priority patent/GB201010509D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract

The present invention relates to a benzodiazepine compound of formula (I), processes for its preparation, pharmaceutical compositions containing such a compound and to its use in therapy.

Description

Benzodiazepine * bromodomain inhibitor
Technical field
The present invention relates to a kind of benzodiazepine compound, its preparation method, containing the pharmaceutical composition of this compound and application in the treatment thereof.
Background technology
Eukaryotic genome is highly organize in nucleus.The long-chain of double-stranded DNA is wound around protein eight aggressiveness (the most usually comprising two copies of histone H2A, H2B, H3 and H4) of histone to form nucleosome.Then, assembled by nucleosome and fold and compress the chromatin Structure that this elementary cell condenses with height of formation further.A series of different state of aggregation is possible, and the tightness of this structure changes in cell cycle process, the tightst during fission process.Chromatin Structure plays keying action in regulatory gene is transcribed, and genetic transcription can not be occurred effectively by the chromatin of high degree of coagulation.By controlling chromatin Structure a series of posttranslational modifications of histone (especially histone H 3 and H4), and modify the most usual in histone afterbody, described afterbody extends beyond core nucleosomal structure.These modifications comprise acetylize, methylate, phosphorylation, ubiquitination and SUMOization.Write and erase these outer genetic markers (epigenetic mark) by certain enzyme, this certain enzyme is by the specific residue of label in histone afterbody, thus form outer genetic coding, then understand to allow the gene specific of chromatin Structure regulate and control and therefore allow to transcribe by cell.
Acetylation of histone is associated with the activation of genetic transcription the most usually, because this modification relaxes the interaction of DNA and octameric histone by changing electrostatics character.Except this physical change, specified protein is combined in acetylizad lysine residue in histone to read outer genetic coding.When histone, bromodomain (bromodomains) is usual but little (~ 110 amino acid) visibly different structural domain in the protein that is combined with acetylizad lysine residue of non-expert.Have the known protein containing bromodomain of gang about 50 kinds, and they has a series of function in cell.
The protein containing bromodomain of Bet race comprises 4 kinds of protein (BRD2, BRD3, BRD4 and BRD-t) containing series connection bromodomain; described series connection bromodomain in conjunction with two tight close acetylated lysine residue, thus can improve interactional specificity.It is reported that BRD2 and BRD3 combines along the gene of active transcription with histone, and may participate in promoting transcription elongation (Leroy etc., Mol.Cell.2008 30 (1): 51-60), and BRD4 seem to participate in be raised by pTEF-B complex body can induced gene, thus cause the phosphorylation of RNA polymerase and transcribe to export increasing (Hargreaves etc., Cell, 2,009 138 (1): 129-145).There was reported BRD4 and BRD3 and NUT (nucleoprotein in testis) to merge and the new fusion oncogene that formed in the high malignancy form of epithelial tumor, BRD4-NUT (the .Cancer Research such as French, 2003,63, the .Journal of Clinical Oncology such as 304-307 and French, 2004,22 (20), 4135-4139).Notes of Key Data BRD-NUT fused protein promotes carcinogenesis (Oncogene, 2008,27,2237-2242).BRD-t only expresses in testis and ovary.It is reported that all family members have some function in the control of cell cycle or execution, and be proved to be maintenance and chromosomal compound during cell fission---the effect in pointing out heredity outside maintaining to remember.In addition, as the part of virus replication, some viruses utilize these protein their genome to be tethered to (Cell such as You, 2,004 117 (3): 349-60) on the chromatin of host cell.
Japanese patent application JP2008-156311 discloses a kind of benzimidizole derivatives, it is said that it is the BRD2 bromodomain bonding agent of the effectiveness had about virus infection/propagation.
Patent application WO2009/084693A1 discloses a series of thieno-triazolo diaza (thienotriazolodiazepiene) derivative, it is said that it suppresses the combination between acetylated histones and the protein containing bromodomain, and allegedly can be used as carcinostatic agent.
Have been found that a kind of bromodomain that suppresses is combined with its homology acetylated protein matter, more specifically suppress the compound that Bet race bromodomain is combined with acetylated lysine residue.Below this compound is called " bromodomain inhibitor ".
Summary of the invention
In a first aspect of the present invention, provide formula (I) compound or its salt
In a second aspect of the present invention, provide the pharmaceutical composition of contained (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle.
In a third aspect of the present invention, provide formula (I) compound or its pharmacy acceptable salt in treatment, particularly need the purposes in the disease of bromodomain inhibitor or illness in treatment.
In a fourth aspect of the present invention, what provide treatment experimenter in need needs the disease of bromodomain inhibitor or the method for illness, and it comprises formula (I) compound or its pharmacy acceptable salt that give to treat significant quantity.
In a fifth aspect of the present invention, providing formula (I) compound or its pharmacy acceptable salt is needing the purposes in the disease of bromodomain inhibitor or the medicine of illness for the preparation for the treatment of.
Detailed Description Of The Invention
The present invention relates to formula (I) compound, it is 2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide
or its salt.
Should understand and present invention covers as free alkali and formula (I) compound as its salt (such as its pharmacy acceptable salt).
Provide a kind of compound in one embodiment, it is 2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide.
Due to they potential uses in medicine, the salt of formula (I) compound is pharmaceutically acceptable ideally.Provide a kind of compound in another embodiment, it is 2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide or its pharmacy acceptable salt.
The pharmacy acceptable salt be applicable to can comprise acid or base addition salt.Be applicable to the summary of salt see Berge etc., J.Pharm.Sci., 66:1-19, (1977).Typically, pharmacy acceptable salt can easily be prepared by the acid needed for use or alkali in due course.The salt obtained can be precipitated and maybe can be evaporated by solvent by collecting by filtration and reclaim from solution.
Pharmaceutically acceptable base addition salt optionally reacts by formula (I) compound and suitable inorganic or organic bases (such as triethylamine, thanomin, trolamine, choline, arginine, Methionin or Histidine) and forms to obtain usually such as by crystallization and the base addition salt filtering to be separated in applicable solvent.Pharmaceutically acceptable subsalt comprises ammonium salt, an alkali metal salt such as sodium salt and sylvite, alkaline earth salt such as calcium salt and magnesium salts and the salt with organic bases, comprises the salt of primary, secondary and tertiary amine (such as Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexyl amine and N-methyl-D-glucosamine).
Pharmaceutically acceptable acid salt is by formula (I) compound and suitable inorganic or organic acid (such as Hydrogen bromide, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succsinic acid, toxilic acid, acetic acid, propionic acid, fumaric acid, citric acid, tartrate, lactic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, aspartic acid, tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, naphthene sulfonic acid is as 2-naphthene sulfonic acid, or caproic acid) optionally in the solvent be applicable to is as organic solvent, reaction forms to obtain usually such as by the salt of crystallization and filtering separation.The pharmaceutically acceptable acid salt of formula (I) compound can comprise, such as, hydrobromate, hydrochloride, vitriol, nitrate, phosphoric acid salt, succinate, maleate, acetate, propionic salt, fumarate, Citrate trianion, tartrate, lactic acid salt, benzoate, salicylate, glutaminate, aspartate, tosilate, benzene sulfonate, mesylate, esilate, naphthalenesulfonate (such as 2-naphthalenesulfonate) or hexanoate.
Acceptable salt in other non-pharmaceutical, such as formate, oxalate or trifluoroacetate, can use, and comprise within the scope of the invention in the separation of such as formula (I) compound.
Scope of the present invention comprises institute's likely stoichiometric form and non-stoichiometric forms of the salt of formula (I) compound.
Should be understood that a lot of organic compound can react with them or from wherein to precipitate or the solvent of crystallization forms mixture wherein.These mixtures are called " solvate ".Such as, be called " hydrate " with the mixture of water.The solvent such as water, dimethylbenzene, N-Methyl pyrrolidone, methyl alcohol and the ethanol that have high boiling point and/or can form hydrogen bond can be used for forming solvate.The method of qualification solvate includes, but not limited to NMR and trace analysis.The solvate of formula (I) compound within the scope of the invention.
Scope of the present invention comprises all possible stoichiometric form and the non-stoichiometric forms of the solvate of formula (I) compound.
All prodrugs of formula (I) compound and its pharmacy acceptable salt are contained in the present invention, and it can provide (directly or indirectly) formula (I) compound or its pharmacy acceptable salt or its active metabolite or residue when giving recipient.This derivative is that those skilled in the art are just discernible without the need to undo experimentation.But, can with reference to the Medicinal Chemistry and DrugDiscovery of Burger, the 5th edition, the 1st volume: the instruction of Principles and Practice, it is herein incorporated with way of reference the degree reaching this analog derivative of instruction.
Formula (I) compound can be crystal or amorphous form.And formula (I) compound of some crystalline form can exist by polymorphic, and it comprises within the scope of the invention.The polymorphic forms of formula (I) compound can use the analytical technology of many routines, includes but not limited to that X-ray powder diffraction (XRPD) spectrum, infrared (IR) spectrum, Raman spectrum, dsc (DSC), thermogravimetric analysis (TGA) and solid state nmr (SSNMR) characterize and distinguish.
Formula (I) compound is the single isomer of separation and is substantially free of other isomer (i.e. enantiomer-pure), to make existence be less than 10%, is preferably less than about 1%, such as, is less than other enantiomorph of about 0.1%.
The separation of isomer is by routine techniques well known by persons skilled in the art, and such as fractional crystallization, chromatography or HPLC realize.
Formula (I) compound can the one in several tautomeric form exist.Should be appreciated that all tautomers of the formula of the present invention includes (I) compound, no matter as single tautomer or as its mixture.
Should be appreciated from the above, scope of the present invention comprises the solvate of formula (I) compound and its salt, isomer and polymorphic form.
Formula (I) compound and its pharmacy acceptable salt, by multiple method, comprise standard chemical effect, preparation.Below list illustrative general synthetic method, and concrete formula (I) compound is prepared in working Examples subsequently.These methods form further aspect of the present invention.
Can according to reaction scheme 1, by making formula (II) compound and EtNH 2at room temperature react and preparation formula (I) compound under HATU or HBTU and DIEA exists.Selectively, by making formula (II) compound and oxalyl chloride react, EtNH is added in the presence of triethyl amine subsequently 2and preparation formula (I) compound.
scheme 1
Can according to reaction scheme 2 preparation formula (II) compound.Suitable reaction conditions comprises makes formula (III) compound and the preferred sodium hydroxide of alkali metal hydroxide or lithium hydroxide react.
scheme 2
Wherein R represents C 1-6alkyl is methyl such as.
Can react and preparation formula (III) compound by making formula (IV) compound and AcOH according to reaction scheme 3.
scheme 3
Can react at lower than 15 DEG C by making formula (VI) compound and hydrazine according to reaction scheme 4, being reacted and preparation formula (IV) compound at 0 DEG C with MeCOCl by the hydrazone (V) of gained subsequently.Usually, hydrazone (V) uses without being further purified, and reacts at such as 0 DEG C with MeCOCl.
scheme 4
Can according to reaction scheme 5 by with lawesson reagent (Lawesson ' s reagent) or P 4s 10process formula (VII) compound and preparation formula (VI) compound, wherein R is C 1-6alkyl (such as methyl).Suitable reaction conditions comprises makes formula (VIII) compound and P 4s 10react at such as 70 DEG C in 1,2-ethylene dichloride.
scheme 5
Can react by making formula (IX) compound and organic bases such as triethylamine according to reaction scheme 6, making the amine (VIII) of gained and acetic acidreaction and preparation formula (VII) compound subsequently.Usually, amine (VIII) uses without being further purified, and reacts at such as 60 DEG C with AcOH.
scheme 6
Can react and preparation formula (IX) compound with the chloride of acid (X) derived from the aspartic acid protected by making formula (XI) compound according to reaction scheme 7.
scheme 7
Can according to process preparation formula (XI) compound described in Synthesis 1980,677-688.Can according to J.Org.Chem., 1990,55,3068-3074 and J.Cehm.Soc.Perkin Trans.1, the chloride of acid of the process preparation formula (X) described in 2001,1673-1695.
Selectively, can according to reaction scheme 8 preparation formula (I) compound.
scheme 8
Wherein R represents C 1-4alkyl is methyl such as.
Can according to reaction scheme 9 by making formula (IVA) compound and EtNH 2react and preparation formula (IIIA) compound under such as room temperature under the existence of HATU and DIEA.
scheme 9
Can according to reaction scheme 10 preparation formula (IVA) compound.Suitable reaction conditions comprises makes formula (VI) compound and alkali metal hydroxide such as sodium hydroxide react.
scheme 10
It will be understood by those skilled in the art that the one or more functional groups protecting the compound described in said process may be favourable.Protecting group and its example removing mode can find in T.W.Greene " Protective Groups in Organic Synthesis " (the 4th edition, J.Wiley and Sons, 2006).The amine protecting group be applicable to comprises acyl group (such as ethanoyl), carbamate (such as 2 '; 2 '; 2 '-tri-chloroethoxy base carbonyl, benzyloxycarbonyl or tert-butoxycarbonyl) and aralkyl (such as benzyl); it can in due course by hydrolysis (such as using the hydrochloric acid in acid such as diox or trifluoroacetic acid in methylene dichloride) or (the zinc reductibility in the hydrogenolysis of such as benzyl or benzyloxycarbonyl or use acetic acid removes 2 ' by reduction mode; 2 ', 2 '-tri-chloroethoxy base carbonyl) and remove.Other amine protecting group be applicable to comprises trifluoroacetyl group (-COCF 3), its hydrolysis by base catalysis removes.
Should understand in any above-mentioned route, the precise sequence of the synthesis step various different group and part introduced in molecule may change.Those skilled in the art can guarantee the group introduced in a stage of described process or part can not by follow-up conversion and reaction affect, and select the order of synthesis step accordingly.
It is believed that some above-mentioned midbody compound is new, and because which form another aspect of the present invention.
Formula (I) compound and its salt are bromodomain inhibitor, and therefore it is believed that and need to have potential utility in the disease of bromodomain or illness in treatment.
Therefore, the invention provides a kind of formula (I) compound or its pharmacy acceptable salt purposes in the treatment.Described formula (I) compound or its salt pharmaceutically can be used for treating the disease or illness that need bromodomain inhibitor.
In one embodiment, formula (I) compound is provided or its pharmacy acceptable salt is used for the treatment of the disease or illness that need bromodomain.In another embodiment, compound is provided or its pharmacy acceptable salt is used for the treatment of chronic auto-immune and/or inflammatory conditions.In further embodiment, provide compound or its pharmacy acceptable salt is used for the treatment of cancer, such as center line cancer (midline carcinoma).
In one embodiment, provide formula (I) compound or its pharmacy acceptable salt and need the purposes in the disease of bromodomain inhibitor or the medicine of illness for the preparation for the treatment of.In another embodiment, formula (I) compound or the purposes of its pharmacy acceptable salt in the medicine for the preparation for the treatment of chronic auto-immune and/or inflammatory conditions is provided.In further embodiment, provide formula (I) compound or its pharmacy acceptable salt for the preparation of Therapeutic cancer, such as, purposes in the medicine of center line cancer.
In one embodiment, provide be used for the treatment of experimenter in need need the disease of bromodomain inhibitor or the method for illness, it comprises formula (I) compound or its pharmacy acceptable salt that give to treat significant quantity.In another embodiment, provide and be used for the treatment of the chronic auto-immune of experimenter in need and/or the method for inflammatory conditions, it comprises formula (I) compound or its pharmacy acceptable salt that give to treat significant quantity.In further embodiment, provide a kind of cancer being used for the treatment of experimenter in need, such as the method for center line cancer, it comprises formula (I) compound or its pharmacy acceptable salt that give to treat significant quantity.
Experimenter in need is Mammals in one embodiment, especially people.
As used herein, term " significant quantity " refers to and can cause just by the amount of the tissue of such as researchist or clinician investigation, system, the biology of animal or human or the medicine of medical response or medicament.In addition, term " treatment significant quantity " refers to compared with the corresponding experimenter not accepting this amount, causes any amount that disease, the further treatment of obstacle or side effect, healing, prevention or improvement or disease or obstacle progression rates reduce.This term also comprises the amount effectively strengthening normal physiological function within the scope of it.
It is believed that bromodomain inhibitor can be used for treatment various diseases or illness, described disease or illness and system or tissue inflammation, to infect or the Inflammatory response of anoxic, cell activation and propagation, lipid metabolism, fibrosis relevant; Be used in prevention and therapy virus infection.
Bromodomain inhibitor can be used for treating multiple chronic auto-immune and inflammatory conditions, such as rheumatoid arthritis, osteoarthritis, acute gout, psoriatic, systemic lupus erythematous, multiple sclerosis, inflammatory bowel (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airway disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous dermatosis, ephritis, vasculitis, atherosclerosis, Alzheimer's disease, dysthymia disorders, the retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, A Disenshi disease, hypophysitis, thyroiditis, the acute rejection of type i diabetes and transplant organ.
Bromodomain inhibitor can be used for treatment various acute inflammation, and such as acute gout, giant cell arteritis, ephritis comprises lupus nephritis, organ participates in vasculitis such as glomerulonephritis, vasculitis comprise the acute rejection of giant cell arteritis, wegener granulomatosis, polyarteritis nodosa, behcets disease, mucocutaneous lymphnode syndrome, multiple takayasu arteritis (Takayasu ' arteritis) and transplant organ.
Bromodomain inhibitor can be used for prevention or treatment relates to bacterium, virus, fungi, the disease of parasite or its toxi-infectious Inflammatory response or illness, such as septicemia, sepsis syndrome, septic shock, endotoxemia, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burn, acute pancreatitis, Post-operative syndrome, sarcoidosis, Herxheimer reaction (Herxheimer reaction), encephalitis, myelitis, meningitis, malaria, with virus infection such as influenza, zoster, the SIRS reaction that herpes simplex is relevant with coronavirus.
Bromodomain inhibitor can be used for preventing or treatment and ischemical reperfusion injury such as myocardial infarction, cerebrovascular ischemia (apoplexy), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass graft surgery, illness that cardiopulmonary bypass art is relevant with lung, kidney, liver, stomach and intestine or periphery limbs embolism.
Bromodomain inhibitor can be used for the disease of the lipid metabolism for the treatment of by regulating APO-A1, such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
Bromodomain inhibitor can be used for treating fibrotic conditions, such as idiopathic pulmonary fibrosis, renal fibrosis, postoperative stenosis, cicatrization, scleroderma and cardiac fibrosis.
Bromodomain inhibitor can be used for prevention and therapy virus infection, such as simplexvirus, Human papilloma virus HPV, adenovirus, poxvirus and other DNA virus.
Bromodomain inhibitor can be used for Therapeutic cancer, comprises blood (such as leukemia), epithelium comprises lung, mammary gland and colon carcinoma, center line cancer, interstitial, liver, kidney and nervous system neoplasm.
Bromodomain inhibitor can be used for treatment ophthalmology indication, such as xerophthalmia.
In one embodiment, the disease of bromodomain inhibitor or illness is needed to be selected from the disease relevant to systemic inflammatory response syndrome, such as septicemia, burn, pancreatitis, significant wound, hemorrhage and local asphyxia.In this embodiment, bromodomain inhibitor should in diagnosis place to the incidence being reduced following situation: SIRS, shock outbreak, multiple organ dysfunction syndrome, it comprises acute lung injury outbreak, ARDS, acute renal, liver, heart and gastrointestinal damage, and death.In another embodiment, bromodomain inhibitor should give before the surgical operation relevant to the high risk of septicemia, hemorrhage, extensive tissue injury, SIRS or MODS or other programs.In special embodiment, the disease of bromodomain inhibitor or illness is needed to be septicemia, sepsis syndrome, septic shock and/or endotoxemia.In another embodiment, described bromodomain inhibitor need be used for the treatment of acute or chronic pancreatitis.In another embodiment, described bromodomain is required for treatment burn.
In one embodiment, need the disease of bromodomain inhibitor or illness to be selected from herpes simplex infections and recurrence, cold sore, herpes zoster virus infection and recurrence, varicella, zoster, Human papilloma virus HPV, cervix neoplasms, adenovirus infection and comprise acute respiratory disease and poxvirus infection such as cowpox and smallpox and African swine fever virus.In a special embodiment, bromodomain inhibitor need be used for the treatment of the human papilloma virus infection of skin or epithelium of cervix uteri.
Term " needs the disease of bromodomain inhibitor or illness " to be intended to comprise any or all above-mentioned morbid state.
When being likely used for the treatment of, formula (I) compound and its pharmacy acceptable salt can be used as precursor chemicals and give, and it is general that activeconstituents exists as pharmaceutical composition.
Therefore, further, the invention provides the pharmaceutical composition of contained (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle.
The disease of bromodomain inhibitor or the pharmaceutical composition of illness is needed, its contained (I) compound or its pharmacy acceptable salt because herein is provided to be used for the treatment of.
Just compatible with other composition of composition and must be acceptable to the harmless aspect of its recipient for the carrier in this pharmaceutical composition, thinner or vehicle.According to a further aspect in the invention, additionally provide the method for pharmaceutical compositions, comprise and make formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or mixed with excipients.Described pharmaceutical composition can be used for treating any illness as herein described.
Because formula (I) compound and its pharmacy acceptable salt are intended to in pharmaceutical composition, should easily understand, they are each preferably with substantially pure, such as at least 60% is pure, be more suitable at least 75% is pure and mild preferably at least 85% pure, and especially the form of at least 98% pure (% by weight of weighing scale) provides.
Pharmaceutical composition can per unit dosage contain the activeconstituents of predetermined amount unit dosage exist.Preferred units dosage composition is those of activeconstituents containing per daily dose or sub-doses or its suitable mark.Therefore, this unitary dose can give once for one day.Preferred units dosage composition is containing those of the herein activeconstituents of per daily dose as above or sub-doses (giving once for a day) or its suitable mark.
Pharmaceutical composition can be adapted to pass through any suitable approach, such as by oral (comprise oral cavity and sublingual), rectum, suction, nose, locally (comprise oral cavity, sublingual or through skin), vagina or parenteral (comprising subcutaneous, intramuscular, intravenously or intracutaneous) approach give.This composition by the known any method of pharmacy field, such as, is prepared by making activeconstituents be combined with one or more carriers or vehicle.
In one embodiment, described pharmaceutical composition is suitable for oral administration.
In one embodiment, described pharmaceutical composition is suitable for parenteral admin, especially intravenously administrable.
The pharmaceutical composition being suitable for parenteral admin comprises water-based and non-aqueous sterile injection solution, its solute that can contain oxidation inhibitor, buffer reagent, fungistat and make described composition isotonic with the blood of expection recipient; And water-based and non-aqueous sterile suspensions, it can comprise suspension agent and thickening material.Described composition at unitary dose or multi-dose container, such as, can exist in sealed ampoule and bottle, and can store under lyophilize (freeze-drying) condition, and it only needs just to add sterile liquid carrier before use, such as water, thus injection.Instant injection solution and suspension can be prepared by sterilized powder, particle and tablet.
Be suitable for the pharmaceutical composition of oral administration with discrete unit such as capsule or tablet; Powder or particle; Solution in water-based or non-aqueous liquid or suspension; Edible foam or whips (whips); Or oil-in-water liquid emulsion or water-in-oil liquid emulsion exist.
Such as, for the oral administration of tablet or capsule form, active pharmaceutical ingredient can with the combinations such as oral, nontoxic pharmaceutically acceptable inert support such as ethanol, glycerine, water.Be suitable for adding powder in tablet or capsule by described compound being decreased to applicable fine size (such as passing through micronization) and mixing with pharmaceutical carrier such as edible the carbohydrate such as starch or N.F,USP MANNITOL of similar preparation and prepare.Also correctives, sanitas, dispersion agent and tinting material can be there is.
By preparing powdered mixture as above and filling the gelcoat of formation and prepare capsule.Before stuffing operation, glidant and lubricant such as silica gel, talcum powder, Magnesium Stearate, calcium stearate or solid polyethylene glycol can be added in powdered mixture.Also disintegrating agent or solubilizing agent such as agar, calcium carbonate or sodium carbonate can be added when taking capsule to improve the availability of medicine.
In addition, when desired or needed, also applicable tackiness agent, glidant, lubricant, sweeting agent, correctives, disintegrating agent and tinting material can be added in this mixture.The tackiness agent be applicable to comprises starch, gelatin, natural sugars as glucose or beta lactose, corn sweetener, natural and synthetic gum such as Sudan Gum-arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax etc.Sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc. are comprised for the lubricant in these formulations.Disintegrating agent includes, but not limited to starch, methylcellulose gum, agar, bentonite, xanthan gum etc.Tablet by such as preparing powdered mixture, granulate or hit pressure (slugging), add lubricant and disintegrating agent and tabletted and preparing.Powdered mixture is by making the compound of suitably pulverizing with thinner as above or matrix and optionally mixing with tackiness agent such as carboxymethyl cellulose, alginates, gelatin or polyvinylpyrrolidone, retarding solvent (solutionretardant) such as paraffin, absorption enhancer such as quaternary salt and/or absorption agent such as bentonite, kaolin or Si Liaodengji dicalcium phosphate feed grade and prepare.Described powdered mixture is by forcing to sieve granulate by the solution-wet of tackiness agent such as syrup, starch paste, Acadia's mucus (acadia mucilage) or Mierocrystalline cellulose or polymeric material.As the replacement scheme of granulating, described powdered mixture can be made to run through pelleter, result is the sheet being broken into particle be not exclusively shaped.Mode lubricated granules by adding stearic acid, stearate, talcum or mineral oil is formed on mould to prevent being bonded at tablet.Then by the mixture tabletted of lubrication.The compounds of this invention also can mix with free-pouring inert support and be directly compressed into tablet and without the need to by granulating or hitting pressure step.Transparent or the opaque coat composed protection dressing of polishing by shellac seal coating, sugar or polymerization material coating and wax can be provided.Dyestuff can be added in these coatings to distinguish different unit dosage.
Liquid oral such as solution, syrup and elixir can be made dosage unit form with the compound making given quantity contain predetermined amount.By compound dissolution is prepared syrup in the aqueous solution of suitable flavoring, and by using nontoxic alcoholic medium to prepare elixir.By compound is dispersed in formulated suspension in nontoxic medium.Also solubilizing agent and emulsifying agent such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ether, sanitas, flavoring additive such as spearmint oil or natural sweeteners or asccharin or other artificial sweetner etc. can be added.
If needed, micro-encapsulating the dosage unit compositions of oral administration can be used for.Also the preparation extending or maintain release can be prepared, such as, by coated or by microparticle material embedded polymer thing, wax etc.
Also can liposome delivery system, form giving construction (I) compound of such as little unilamellar vesicle, large unilamellar vesicle and multilamellar vesicle and its pharmacy acceptable salt.Can by multiple phosphatide, such as cholesterol, stearylamine or Yelkin TTS form liposome.
The pharmaceutical composition being suitable for topical can be mixed with ointment, creme, suspensoid, lotion, pulvis, solution, paste, gelifying agent, sprays, aerosol or oil.
Such as, in order to treat eyes or other outside organization, mouth and skin, described composition is preferably with topical ointment or creme application.When being mixed with ointment, activeconstituents can use together with paraffinic or the mixable ointment base of water.Selectively, activeconstituents can be mixed with creme together with Oil-in-water creams matrix or water-in-oil matrix.
Being suitable for topical in the pharmaceutical composition of eyes comprises eye drops, wherein by solubilize active ingredients or be suspended in suitable carrier, especially in aqueous solvent.
Formulation for intranasal or inhalation can be mixed with aerosol, solution, suspensoid, gelifying agent or dry powder doses easily.
For be applicable to and/or the composition that is adapted to inhalation, preferred described formula (I) compound or its pharmacy acceptable salt are the form that the particle diameter such as obtained by micronization is reduced.Size reduces the compound of (such as micronized) or the preferable particle size of salt defines (such as using determination of laser diffraction) by the D50 value of about 0.5-about 10 microns.
Such as can comprise the solution of active substance pharmaceutically in acceptable water-based or non-aqueous solvent or thin suspension for the aerosol of inhalation.Aerosol can the sterile form of single dose or multiple doses be present in sealed vessel, and it can adopt medicine box or the form that recharges for using together with spraying plant or sucker.Selectively, sealing container can be single assigned device, such as single dose nasal inhaler or be equipped with the spray dispenser (metered dose inhaler) of metering valve, and its content is in a reservoir depleted to be dropped.
When formulation comprises aerosol dispenser, it is preferably containing the pressurized propellant be applicable to, such as pressurized air, carbonic acid gas or organic propelling agent such as hydrofluorocarbons (HFC).The HFC propelling agent be applicable to comprises HFC-227ea and HFA 134a.Aerosol dosage forms also can adopt the form of pump sprayer.Pressurised aerosol can comprise solution or the suspension of active compound.This may need to add extra vehicle, and such as solubility promoter and/or tensio-active agent are to improve dispersing characteristic and the uniformity of suspension formulations.Pharmaceutical solutions also may need to add solubility promoter, such as ethanol.
For be applicable to and/or the pharmaceutical composition that is adapted to inhalation, described pharmaceutical composition can be dry powder can composition for inhalation.This composition can comprise powdered substrate, such as lactose, glucose, trehalose, N.F,USP MANNITOL or starch, formula (I) compound or its pharmacy acceptable salt (preferably with the form that particle diameter reduces, such as, with Micronised form) and optional performance modifier such as L-Leu or another amino acid and/or Metallic stearates such as Magnesium Stearate or calcium stearate.Preferably, described dry powder can comprise the powder mixture of lactose such as Spherolac 100 and formula (I) compound or its pharmacy acceptable salt by composition for inhalation.Applicable equipment such as DISKUS can be used this composition is given patient by equipment, and described equipment is sold by GlaxoSmithKline, and it describes in such as GB2242134A.
Formula (I) compound and its pharmacy acceptable salt can be mixed with liquid preparation, with from liquid dispenser, such as there is the liquid dispenser of distribution nozzle or distribution openings (dosing by its distributing liquid preparation), being delivered to the pump structure of liquid dispenser when applying the strength of user.This liquid dispenser provides the bank of multiple dosings of liquid preparation usually, and this dosage can activate through order pump and send.Distribution nozzle or distribution openings can be set to insert in the nostril of user, so that liquid preparation spraying is dispensed into nasal cavity.The liquid dispenser of the above-mentioned type describes and illustrates in WO2005/044354A1.
The treatment significant quantity of formula (I) compound or its pharmacy acceptable salt will depend on many factors, such as comprise, the precise condition that the age of animal and weight, needs are treated and its severity, preparation nature and route of administration, and will finally be determined by doctor in charge or animal doctor.In pharmaceutical composition, preferably contain formula (I) compound or its pharmacy acceptable salt calculated with free alkali of 0.01-3000mg, more preferably 0.5-1000mg for each dose unit that is oral or parenteral admin.For formula (I) compound preferably containing 0.001-50mg, more preferably 0.01-5mg of each dose unit of intranasal or inhalation or its pharmacy acceptable salt calculated with free alkali.
Can per daily dose (for adult patients) giving construction (I) compound and its pharmacy acceptable salt, such as, the 0.01mg-3000mg every day of formula (I) compound or its pharmacy acceptable salt calculated with free alkali or the oral or parenteral dose of 0.5-1000mg every day, or the intranasal of 0.001-50mg every day or 0.01-5mg every day or inhalation dose.This amount can every day with single dose administration or more generally every day with multiple (such as two, three, four, five or six) sub-doses administration to make total per daily dose identical.The significant quantity of its pharmacy acceptable salt can be determined with the ratio of the significant quantity of formula (I) compound own.
Because herein is provided a kind of pharmaceutical composition, comprise formula (I) compound or its pharmacy acceptable salt of a) 0.01-3000mg, and one or more pharmaceutically acceptable carrier, thinner and/or vehicle of b) 0.1-2g.
Formula (I) compound and its pharmacy acceptable salt can be used alone or with other treatment agent conbined usage.Therefore, conjoint therapy of the present invention comprises and gives at least one formula (I) compound or its pharmacy acceptable salt, and uses other forms of pharmacologically active agents of at least one.Preferably, conjoint therapy of the present invention comprises and gives at least one formula (I) compound or its pharmacy acceptable salt, and other forms of pharmacologically active agents of at least one.Formula (I) compound and its pharmacy acceptable salt, can give or give separately together with single medicine composition, and when giving separately, this can occur simultaneously or in succession occurs with any order with other forms of pharmacologically active agents.By selecting type (I) compound and the amount of pharmacy acceptable salt and other forms of pharmacologically active agents and the relative time of administration, to realize the combined therapy effect of wishing.Therefore, further, the composition of contained (I) compound or its pharmacy acceptable salt and other forms of pharmacologically active agents of at least one is provided.In one embodiment, the medicinal composition product of contained (I) compound or its pharmacy acceptable salt and one or more other treatment promoting agents is provided.
Therefore in one aspect, formula (I) compound and pharmaceutical composition can use with one or more combination with other therapeutic agents or comprise one or more other treatment agent, and described other treatment agent is such as selected from microbiotic, antiviral agent, glucocorticosteroid, muscarine antagonist and β-2 agonist.
Should understand when formula (I) compound and its pharmacy acceptable salt and other usually pass through to suck, the therapeutic agent administration of intravenously, oral or nasal administration time, the pharmaceutical composition obtained is by identical administration.Selectively, the single composition of composition is by different approaches administration.
An embodiment of the invention include the composition comprising one or both other treatment agent.
It should be apparent to those skilled in the art that, if needed, other treatment composition can the form of salt (such as alkali metal salts or ammonium salt or as acid salt) or prodrug or ester (such as lower alkyl esters) or solvate (such as hydrate) use, such as, to optimize the activity of described therapeutic component and/or stability and/or physical property, solvability.It is also to be appreciated that if needed, described therapeutic component can optically pure form use.
Above-described composition can exist with the form of pharmaceutical composition easily in order to use, and the pharmaceutical composition therefore comprising composition as above and pharmaceutically acceptable diluent or carrier represents further aspect of the present invention.
By method as described below or by similar approach preparation formula (I) compound.Therefore, following intermediate and embodiment in order to illustrate the preparation of formula (I) compound, and should not be considered to limit the scope of the invention by any way.
Embodiment
general experimental details
The all temperature related to are DEG C.
Abbreviation
lC/MSrefer to the analysis by analysis mode HPLC carried out on two kinds of instruments:
A) on Supelcosil LCABZ+PLUS post (3 μm, 3.3cmx4.6mm ID), with 0.1%HCO 2the aqueous solution (solvent orange 2 A) of H and 0.01M ammonium acetate, and 95% acetonitrile and 0.05%HCO 2the aqueous solution (solvent B) wash-out of H, use following gradient 0-0.7 minute 0%B, 0.7-4.2 minute 0 → 100%B, 4.2-5.3 minute 100%B, 5.3-5.5 minute 100 → 0%B, flow velocity is 3mL/ minute.On Fisons VG Platform mass spectrograph, [(ES+ve is to provide [M+H] to use electrospray just to ionize +[M+NH 4] +molion] or electrospray negative electricity from [(ES-ve is to provide [M-H] -molion] mode record mass spectrum (MS).Analytical data from this instrument provides with following form: [M+H] +or [M-H] -.
B) on Chromolith Performance RP 18 post (100x4.6mm id), with the aqueous solution of 0.01M ammonium acetate (solvent orange 2 A) and 100% acetonitrile (solvent B) wash-out, use following gradient: 0-4 minute 0 → 100%B, 4-5 minute 100%B, flow velocity is 5mL/ minute.On micromass Platform-LC mass spectrograph, [AP+ve is to provide MH to use atmospheric pressure chemical just to ionize +molion] or atmospheric pressure chemical negative electricity from [AP-ve is to provide (M-H) -molion] mode record mass spectrum (MS).Analytical data from this instrument provides with following form: with [M+H] that the APCI that abridges is preposition +or [M-H] -indicate this two mass spectroscopy sources.
lC/HRMS:analysis mode HPLC carries out on Uptisphere-hsc post (3 μm of 33x3mm id), with the aqueous solution of 0.01M ammonium acetate (solvent orange 2 A) and 100% acetonitrile (solvent B) wash-out, use following gradient: 0-0.5 minute 5%B, 0.5-3.75 minute 5 → 100%B, 3.75-4.5 100%B, 4.5-5 100 → 5%B, 5-5.5 5%B, flow velocity is 1.3mL/ minute.On micromass LCT mass spectrograph, [ES+ve is to provide MH to use electrospray just to ionize +molion] or electrospray negative electricity from [ES-ve is to provide (M-H) -molion] mode record mass spectrum (MS).
the directed preparative HPLC automatically of qualityrefer to the method for material by high-efficient liquid phase chromatogram purification, described high performance liquid chromatography carries out on HPLCABZ+5 μm of post (5cmx10mm i.d.), uses 0.1%HCO 2the aqueous solution of H and 95%MeCN, 5% water (0.5%HCO 2h), utilize following condition of gradient elution: 0-1.0 minute 5%B, 1.0-8.0 minute 5 → 30%B, 8.0-8.9 minute 30%B, 8.9-9.0 minute 30 → 95%B, 9.0-9.9 minute 95%B, 9.9-10 minute 95 → 0%B, flow velocity is 8mL/ minute.Gilson202 fraction collector device is triggered when aimed quality being detected by VG Platform mass spectrograph.
proton N MR( 1h NMR) spectrum at room temperature record on Bruker Avance 300DPX spectrometer, use solvent as internal standard substance, the chemical shift of proton in instruction solvent represents with ppm.Following abbreviation is used for the multiplicity of NMR signal: s=is unimodal, d=doublet, t=triplet, q=quartet, dd=double doublet, m=multiplet.
tLC(thin-layer chromatography) refers to the TLC plate using Merck to sell, described plate coating silica gel 60F254.
Embodiment 1:2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide
To [(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine under room temperature -4-base] the THF solution of acetic acid (preparing see intermediate 1) (16.0g, 40mmol) adds DIEA (14mL, 80mmol), adds HATU (30.4g, 80mmol) subsequently.Stir this reaction mixture 3h at this temperature and add ethamine (the THF solution of 40mL, 2M, 80mmol).This mixture stirs 48h, subsequently concentrating under reduced pressure.This is slightly material suspended in water, extract with DCM.Organic layer Na 2sO 4dry, filtration also vacuum concentration.Thick solid passes through SiO 2on chromatogram (DCM/MeOH 95/5) purifying, by gained solid recrystallization in MeCN.Then by this dissolution of solid in DCM, and use i-Pr 2o precipitation is with the title compound (8g, productive rate 47%) obtaining white solid.
R f＝0.48(DCM/MeOH：90/10)。M p> 140 DEG C (becoming gluing). 1h NMR (300MHz, CDCl 3) δ 7.53-7.47 (m, 2H), 7.39 (d, J=8.9Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (dd, J=2.9 and 8.9Hz, 1H), 6.86 (d, J=2.9Hz, 1H), 6.40 (m, 1H), 4.62 (m, 1H), 3.80 (s, 3H), 3.51 (dd, J=7.3 and 14.1Hz, 1H), 3.46-3.21 (m, 3H), 2.62 (s, 3H), 1.19 (t, J=7.3Hz, 3H).LC/MS:m/z 424 [M ( 35cl)+H] +, Rt 2.33 minutes.
Intermediate 1:[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] acetic acid
To [(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine under room temperature -4-base] THF (450mL) solution of methyl acetate (preparing see intermediate 2) (28g, 68mmol) adds 1N NaOH (136mL, 136mmol).This reaction mixture stirs 5h at such a temperature, cools subsequently, and with 1N HCl (136mL) cancellation.THF is removed in decompression, and water layer DCM extracts.The organic layer Na merged 2sO 4dry, filtration also concentrating under reduced pressure.Thick solid is at CH 3in CN, recrystallization is to obtain pale yellow powder shape title compound (23.9g, productive rate 89%). 1h NMR (300MHz, CDCl 3) δ 7.55-7.48 (m, 2H), 7.41 (d, J=8.9Hz, 1H), 7.38-7.31 (m, 2H), 7.22 (dd, J=2.9 and 8.9Hz, 1H), 6.90 (d, J=2.9Hz, 1H), 4.59 (dd, J=6.9 and 6.9Hz, 1H), 3.81 (s, 3H), 3.70 (dd, J=6.9 and 25.7Hz, 1H), 3.61 (dd, J=6.9 and 25.7Hz, 1H), 2.63 (s, 3H).LC/MS:m/z 397 [M ( 35cl)+H] +, Rt 2.11 minutes.
Intermediate 2:[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] methyl acetate
By rough [(3S)-2-[(1Z)-2-acetyl hydrazine]-5-(4-chloro-phenyl-)-7-(methoxyl group)-3H-1,4-benzodiazepine under room temperature -3-base] methyl acetate (preparing see intermediate 3) (34g, 79mmol) is suspended in THF (200mL), and adds AcOH (200mL).This reaction mixture stirs at such a temperature and spends the night, and is concentrated into dry subsequently.Resistates is suspended in saturated NaHCO 3, and extract with DCM.Organic layer Na 2sO 4dry, filtration also vacuum concentration.Thick solid passes through SiO 2on chromatogram (DCM/MeOH:90/10) purifying to obtain yellow powder title compound (28g, productive rate 86%).
1h NMR (300MHz, CDCl 3) δ 7.54-7.47 (m, 2H), 7.40 (d, J=8.8Hz, 1H), 7.37-7.31 (m, 2H), 7.22 (dd, J=2.8 and 8.8Hz, 1H), 6.89 (d, J=2.8Hz, 1H), 4.61 (dd, J=6.4 and 7.8Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.66 (dd, J=7.8 and 16.9Hz, 1H), 3.60 (dd, J=6.4 and 16.9Hz, 1H), 2.62 (s, 3H).LC/MS m/z 411 [M ( 35cl)+H] +, Rt 2.88 minutes.
Intermediate 3:[(3S)-2-[2-acetyl hydrazine]-5-(4-chloro-phenyl-)-7-(methoxyl group)-3H-1,4-benzodiazepine -3-base] methyl acetate
To [(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-sulfo--2,3-dihydro-1H-1,4-benzodiazepine at 0 DEG C -3-base] suspension dropping hydrazine monohydrate (11.3mL, 233mmol) of methyl acetate (preparing see intermediate 4) (30.2g, 77.7mmol) in THF (800mL).Stir this reaction mixture 4h at 0-15 DEG C, be cooled to 0 DEG C subsequently.Then slowly Et is added 3n (32.4mL, 230mmol), and drip AcCl (16.3mL, 230mmol).Mixture is warming up to room temperature, stirs 1h, go out and concentrating under reduced pressure with shrend subsequently.Then gained water layer is extracted, organic layer Na with DCM 2sO 4also vacuum concentration is to obtain thick title compound (34g, productive rate 100%) for drying, filtration, and this compound uses without being further purified.LC/MS:m/z 429 [M ( 35cl)+H] +, Rt 2.83 minutes.
Intermediate 4:[(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-sulfo--2,3-dihydro-1H-1,4-benzodiazepine -3-base] methyl acetate
Stirred at ambient temperature P 4s 10(85.8g, 190mmol) and Na 2cO 3(20.5g, 190mmol) suspension 1h in 1,2-DCE (1.5L), then adds [(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine -3-base] methyl acetate (preparing see intermediate 5) (40g, 107mmol).Gained mixture stirs 4h at 65 DEG C, cools subsequently and filters.Wash solid with DCM and use saturated NaHCO 3wash filtrate.Organic layer Na 2sO 4dry, filtration also concentrating under reduced pressure.From DCM/i-Pr 2precipitate title compound in O mixture and filter.Then this filtrate concentrated, and with flash chromatography (DCM/MeOH:98/2) purifying to obtain another batch of product.Merge these two portions and obtain yellow powder title compound (30.2g, productive rate 73%).LC/MS:m/z 389 [M ( 35cl)+H] +, Rt 3.29 minutes.
Intermediate 5:[(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine -3-base] methyl acetate
To thick N 1-[2-[(4-chloro-phenyl-) carbonyl]-4-(methoxyl group) phenyl]-N 2dCM (500mL) solution of-{ [(9H-fluorenes-9-ylmethyl) oxygen base] carbonyl }-L-α-l-asparagine methyl esters (preparing see intermediate 6) (assuming that 0.2mol) adds Et 3n (500mL, 3.65mol), gained mixture backflow 24h, then concentrates.Thick for gained amine is dissolved in 1,2-DCE (1.5L) and also carefully adds AcOH (104mL, 1.8mol).Then at 60 DEG C, this reaction mixture 2h is stirred, subsequently vacuum concentration being dissolved in DCM.Wash organic layer with 1N HCl and use DCM (x3) aqueous layer extracted.The organic layers with water merged and salt solution wash twice, Na 2sO 4dry, filtration also concentrating under reduced pressure.Thick solid recrystallization in MeCN, thus the title compound (51g) obtaining faint yellow solid.Filtrate can concentrate, and in MeCN recrystallization to obtain the intermediate 9 (amount to: 61g, the productive rate based on the intermediate 12 reclaimed is 69%) of other 10g.R f＝0.34(DCM/MeOH：95/5)。LC/MS:m/z 373 [M ( 35cl)+H] +, Rt 2.76 minutes.
Intermediate 6:N 1-[2-[(4-chloro-phenyl-) carbonyl]-4-(methoxyl group) phenyl]-N 2-{ [(9H-fluorenes-9-ylmethyl) oxygen base] carbonyl }-L-α-l-asparagine methyl esters
Methyl N-{ [(9H-fluorenes-9 ylmethyl) oxygen base] carbonyl }-L-α-aspartoyl chlorine is stirred (by J.Org.Chem.1990 at 60 DEG C, 55,3068-3074 and J.Chem.Soc.Perkin Trans.12001, prepared by 1673-1695) (221g, 0.57mol) and [2-amino-5-(methoxyl group) phenyl] (4-chloro-phenyl-) ketone (preparing see intermediate 7) (133g, 0.5mol) at CHCl 3(410mL) the mixture 1.5h in, the also concentrating under reduced pressure of cooling subsequently, uses when not being further purified.LC/MS:m/z 613 [M ( 35cl)+H] +, Rt=3.89 minute.
Intermediate 7:[2-amino-5-(methoxyl group) phenyl] (4-chloro-phenyl-) ketone
To 2-methyl-6-(methoxyl group)-4H-3 at 0 DEG C, 1-benzoxazine-4-ketone (preparing see intermediate 8) (40.0g, solution 0.21mol) in toluene (560mL)/ether (200mL) mixture drips 4-chlorophenylmagnesium bromide solution, and (170mL, 1M are in Et 2in O, 0.17mol).Make this reaction mixture be warming up to room temperature, stir 1h, use 1N HCl cancellation subsequently.By EtOAc (3x) aqueous layer extracted, the organics washed with brine of merging, Na 2sO 4dry, filtration also concentrating under reduced pressure.Then crude compound is dissolved in EtOH (400mL), adds 6N HCl (160mL).Reaction mixture refluxed 2h, then concentrating under reduced pressure.Filter gained solid, wash twice with ether, be then suspended in EtOAc, and neutralize with 1N NaOH.By EtOAc (3x) aqueous layer extracted, the organics washed with brine of merging, Na 2sO 4dry, filtration also concentrating under reduced pressure.Obtain the title compound (39g, productive rate 88%) of yellow solid, this compound is not further purified and uses.
Intermediate 8:2-methyl-6-(methoxyl group)-4H-3,1-benzoxazine-4-ketone
Make the solution of 5-methoxyl group anthranilic acid (7.8g, 46.5mmol) backflow 2h15 in diacetyl oxide (60mL), the also concentrating under reduced pressure of cooling subsequently.Then the concentrated thick resistates twice of gained under toluene exists, subsequent filtration, with ether washing with the title compound (6.8g, productive rate 77%) obtaining beige solid; LC/MS:m/z 192 [M+H] +, Rt 1.69 minutes.
the preparation of Bioexperiment reference compound used
The experimental detail of involved LC-MS method A and B is as follows herein:
LC/MS (method A) carries out, with 0.1%HCO on Supelcosil LCABZ+PLUS post (3 μm, 3.3cmx4.6mm ID) 2the aqueous solution (solvent orange 2 A) of H and 0.01M ammonium acetate, and 95% acetonitrile and 0.05%HCO 2the aqueous solution (solvent B) wash-out of H, uses following gradient: 0-0.7 minute 0%B, 0.7-4.2 minute 0 → 100%B, 4.2-5.3 minute 100%B, 5.3-5.5 minute 100 → 0%B, flow velocity is 3mL/ minute.On Fisons VG Platform mass spectrograph, [(ES+ve is to provide [M+H] to use electrospray just to ionize +[M+NH 4] +molion] or electrospray negative electricity from [(ES-ve is to provide [M-H] -molion] mode record mass spectrum (MS).Analytical data from this instrument provides with following form: [M+H] +or [M-H] -.
LC/MS (method B) carries out under 30 degrees Celsius on Sunfire C18 post (filling diameter for 30mmx4.6mmi.d.3.5 μm), with 0.1%v/v trifluoroacetic acid aqueous solution (solvent orange 2 A) and 0.1%v/v trifluoroacetic acid acetonitrile solution (solvent B) wash-out, use following gradient: 0-0.1 minute 3%B, 0.1-4.2 minute 3-100%B, 4.2-4.8 minute 100%B, 4.8-4.9 minute 100-3%B, 4.9-5.0 minute 3%B, flow velocity is 3mL/ minute.UV detection is the average signal of wavelength 210nm-350nm, and on mass spectrograph, use positive electrospray ionisation record mass spectrum.Ionization data are rounded up to immediate integer.
LC/HRMS: analysis mode HPLC carries out on Uptisphere-hsc post (3 μm of 33x3mm id), with the aqueous solution of 0.01M ammonium acetate (solvent orange 2 A) and 100% acetonitrile (solvent B) wash-out, use following gradient: 0-0.5 minute 5%B, 0.5-3.75 minute 5 → 100%B, 3.75-4.5 100%B, 4.5-5 100 → 5%B, 5-5.5 5%B, flow velocity is 1.3mL/ minute.On micromass LCT mass spectrograph, [ES+ve is to provide MH to use electrospray just to ionize +molion] or electrospray negative electricity from [ES-ve is to provide (M-H) -molion] mode record mass spectrum (MS).
TLC (thin-layer chromatography) refers to the TLC plate using Merck to sell, described plate coating silica gel 60F254.
Silica chromatography technology is included in pre-filled box (SPE) or manual fills automatization (Flashmaster or Biotage SP4) technology on quick post or manual chromatogram.
Reference compound A:2-methyl-6-(methoxyl group)-4H-3,1-benzoxazine-4-ketone
Make the solution (41.8g, 0.25mol) of 5-methoxyl group anthranilic acid (Lancaster) backflow 3.5h, subsequently concentrating under reduced pressure in diacetyl oxide (230mL).Then concentrated crude compound twice under toluene exists, subsequent filtration, ether wash twice the title compound (33.7g, productive rate 71%) obtaining brown solid; LC/MS (method A): m/z 192 [M+H] +, Rt 1.69 minutes.
Reference compound B:[2-amino-5-(methoxyl group) phenyl] (4-chloro-phenyl-) ketone
To 2-methyl-6-(methoxyl group)-4H-3 at 0 DEG C, 1-benzoxazine-4-ketone (preparing see reference compound A) (40.0g, solution 0.21mol) in toluene/ether (2/1) mixture (760mL) drips 4-chlorophenylmagnesium bromide solution, and (170mL, 1M are in Et 2in O, 0.17mol).This reaction mixture is warming up to room temperature, stirs 1h, use 1N HCl (200mL) cancellation subsequently.By EtOAc (3x150mL) aqueous layer extracted, organic layer washed with brine (100mL) washing of merging, Na 2sO 4dry, filtration also concentrating under reduced pressure.Then crude compound is dissolved in EtOH (400mL), adds 6N HCl (160mL).Reaction mixture refluxed 2h, is then concentrated into 1/3rd of volume.Filter gained solid, ether washes twice, and is then suspended in EtOAc, and neutralizes with 1N NaOH.By EtOAc (3x150mL) aqueous layer extracted, organism salt solution (150mL) washing of merging, Na 2sO 4dry, filtration also concentrating under reduced pressure.Obtain the title compound (39g, productive rate 88%) of yellow solid; LC/MS (method A): m/z 262 [M+H] +, Rt 2.57 minutes.
Reference compound C:N 1-[2-[(4-chloro-phenyl-) carbonyl]-4-(methoxyl group) phenyl]-N 2-{ [(9H-fluorenes-9-ylmethyl) oxygen base] carbonyl }-L-α-l-asparagine methyl esters
Methyl N-{ [(9H-fluorenes-9-ylmethyl) oxygen base] carbonyl }-L-α-aspartoyl chlorine (Int.J.Peptide Protein Res.1992,40,13-18) (93g, 0.24mol) is dissolved in CHCl 3(270mL) in, and [2-amino-5-(methoxyl group) phenyl] (4-chloro-phenyl-) ketone (preparing see reference compound B) (53g, 0.2mol) is added.Gained mixture stirs at 60 DEG C, cools, is concentrated into 60% of volume subsequently.Add ether at 0 DEG C, filter gained and precipitate and abandon.Concentrating under reduced pressure filtrate, is not further purified and uses.
Reference compound D:[(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine -3-base] methyl acetate
To N 1-[2-[(4-chloro-phenyl-) carbonyl]-4-(methoxyl group) phenyl]-N 2dCM (500mL) solution of-{ [(9H-fluorenes-9-ylmethyl) oxygen base] carbonyl }-L-α-l-asparagine methyl esters (preparing see reference compound C) (assuming that 0.2mol) adds Et 3n (500mL, 3.65mol), by gained mixture backflow 24h, then concentrates.Thick for gained amine is dissolved in 1,2-DCE (1.5L), carefully adds AcOH (104mL, 1.8mol).Then this reaction mixture is stirred 2h at 60 DEG C, subsequently vacuum concentration being dissolved in DCM.Organic layer is washed, by DCM (x3) aqueous layer extracted with 1N HCl.The organic layers with water merged and salt solution wash twice, Na 2sO 4dry, filtration also concentrating under reduced pressure.Thick solid recrystallization in MeCN, thus the title compound (51g) obtaining faint yellow solid.Filtrate can concentrate, and in MeCN recrystallization to obtain product needed for other 10g.R f＝0.34(DCM/MeOH：95/5)。C 19h 18 35clN 2o 4hRMS (M+H) +calculated value is 373.0955; Measured value is 373.0957.
Reference compound E:[(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-sulfo--2,3-dihydro-1H-1,4-benzodiazepine -3-base] methyl acetate
Stirred at ambient temperature P 4s 10(36.1g, 81.1mmol) and Na 2cO 3(8.6g, 81.1mmol) suspension 2h in 1,2-DCE (700mL), then adds [(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine -3-base] methyl acetate (preparing see reference compound D) (16.8g, 45.1mmol).Gained mixture stirs 2h at 70 DEG C, cools subsequently and filters.Wash solid twice with DCM, use saturated NaHCO 3with salt solution wash filtrate.Organic layer Na 2sO 4dry, filtration also concentrating under reduced pressure.With this crude product of flash chromatography on silica gel (DCM/MeOH:99/1) purifying to obtain the title compound (17.2g, productive rate 98%) of micro-yellow solid.LC/MS (method A): m/z 389 [M ( 35cl)+H] +, Rt 2.64 minutes.
C 19h 18 35clN 2o 3the HRMS (M+H) of S +calculated value is 389.0727; Measured value is 389.0714.
Reference compound F:[(3S)-2-[2-acetyl hydrazine]-5-(4-chloro-phenyl-)-7-(methoxyl group)-3H-1,4-benzodiazepine -3-base] methyl acetate
To [(3S)-5-(4-chloro-phenyl-)-7-(methoxyl group)-2-sulfo--2,3-dihydro-1H-1,4-benzodiazepine at 0 DEG C -3-base] suspension dropping hydrazine monohydrate (3.4mL, 69.6mmol) of methyl acetate (preparing see reference compound E) (9.0g, 23.2mmol) in THF (300mL).This reaction mixture stirs 5h at 5-15 DEG C, is cooled to 0 DEG C subsequently.Then slowly Et is added 3n (9.7mL, 69.6mmol), and drip Acetyl Chloride 98Min. (7.95mL, 69.6mmol).Then mixture is warming up to room temperature 16h, subsequently concentrating under reduced pressure.Crude product to be dissolved in DCM and to wash with water.Organic layer Na 2sO 4also vacuum concentration is to obtain thick title compound (9.7g, productive rate 98%) for drying, filtration, and this crude compound uses without being further purified.R f＝0.49(DCM/MeOH：90/10)。
Reference compound G:[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] methyl acetate
Will thick [(3S)-2-[(1Z)-2-acetyl hydrazine]-5-(4-chloro-phenyl-)-7-(methoxyl group)-3H-1,4-benzodiazepine under room temperature -3-base] methyl acetate (preparing see reference compound F) (assuming that 9.7g) is suspended in THF (100mL), and adds AcOH (60mL).This reaction mixture stirs 2 days at such a temperature, subsequently concentrating under reduced pressure.In i-Pr 2grind thick solid in O and filter with the title compound (8.7g, the productive rate 91% of three steps) obtaining pale solid.
C 21h 20clN 4o 3hRMS (M+H) +calculated value is 411.1229; Measured value is 411.1245.
Reference compound H:[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] acetic acid
To [(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine under room temperature -4-base] THF (130mL) solution of methyl acetate (preparing see reference compound G) (7.4g, 18.1mmol) adds 1N NaOH (36.2mL, 36.2mmol).This reaction mixture stirs 5h at such a temperature, uses 1N HCl (36.2mL) cancellation subsequently and vacuum concentration.Then water is added, water layer DCM (x3) extraction, the organic layer Na of merging 2sO 4dry, filter and concentrating under reduced pressure to obtain the title compound (7g, productive rate 98%) of faint yellow solid.
Reference compound I:[5-({ [(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] ethanoyl } amino) amyl group] carboxylamine 1,1-dimethylethyl esters
Stirred at ambient temperature [(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] acetic acid (preparing see reference compound H) (1.0g, 2.5mmol), HATU (1.9g, 5mmol) with DIPEA (0.88ml, mixture 5mmol) 80 minutes, add (4-aminobutyl) carboxylamine 1 wherein, 1-dimethylethyl esters (1.05ml, 5.0mmol derive from Aldrich).This reaction mixture at room temperature stirs 2 hours, concentrates subsequently.Resistates is dissolved in methylene dichloride, washs with 1N HCl.Water layer dichloromethane extraction twice.Organic layer 1N sodium hydroxide washing, subsequently by sodium chloride saturated solution washing, dried over sodium sulfate concentrated.Utilize the flash chromatography on silica gel Purification using methylene chloride/methanol 95/5, to obtain the title compound (1.2g) of yellow solid.LC/MS (method A): rt=3.04 minute.
Reference compound J:N-(5-Aminopentyl)-2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] acetamide trifluoroacetate
To [5-({ [(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine at 0 DEG C -4-base] ethanoyl } amino) amyl group] carboxylamine 1; 1-dimethylethyl esters (preparing see reference compound H) (0.2g; methylene dichloride (3ml) solution 0.34mmol) drips trifluoroacetic acid (0.053ml, 0.68mmol).At 0 DEG C to this reaction mixture of stirred at ambient temperature 3h.This reaction mixture is concentrated into dry to obtain moisture absorption title compound as yellow oil (200mg).
LC/MS (method A): rt=2.33 minute.
C 25h 29clN 6o 2hRMS (M+H) +calculated value is 481.2119; Measured value is 481.2162.
Reference compound K:Alexa Fluor 488-N-(5-Aminopentyl)-2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] mixture of 5-and 6-isomer of ethanamide
By N-(5-Aminopentyl)-2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base] acetamide trifluoroacetate (preparing see reference compound J) (7.65mg, 0.013mmol) be dissolved in N, in dinethylformamide (DMF) (300 μ l), and the Alexa Fluor 488 carboxylic acid succinimide ester (5mg joined in Eppendorf centrifuge tube, 7.77 μm ol, the mixture of 5 and 6 isomer, derives from Invitrogen, production code member A-20100) in.Add Hunig alkali (7.0 μ l, 0.040mmol), mixture vortex mixed is spent the night.This reaction mixture is evaporated to dry after 18h, resistates is dissolved in DMSO/ water (50% again, amount to < 1ml) in, be applied to preparative Phenomenex Jupiter C18 post, with 95%A: 5%B to the 100%B (aqueous solution of A=0.1% trifluoroacetic acid, B=0.1%TFA/90% acetonitrile/10% water) gradient elution 150 minutes, flow velocity is 10ml/ minute.Merge impure fraction, and use identical system repurity.Merge fraction, and evaporation is to obtain the title compound (2.8mg) as shown two kinds of position different structure mixtures.
LC/MS (method B): MH+=999, rt=1.88 minute.
biological test method
fluorescence anisotropy Binding experiment
Use the combination of fluorescence anisotropy Binding experiment assessment formula (I) compound and bromodomain 2,3 and 4.
By the test compounds of bromodomain albumen, fluorescent ligand (see above-mentioned reference compound K) and variable concentrations under the following conditions common incubation to reach thermodynamic(al)equilibrium: make when existing without test compounds fluorescent ligand significantly (> 50%) combination and when effective inhibitor of enough concentration exists the anisotropy of non-combined with fluorescent part different significantly from associated value.
All data high relative to 16 on each plate with the standardizing average values of the low control wells of 16.Then four parameter curves of following form are applied:
y＝a+(b-a)/(1+(10^x/10^c)^d)
Wherein ' a ' is minimum value, and ' b ' is Hill slope, ' c ' for pIC50 and ' d ' be maximum value.
Have in six histidine-tagged recombinant human bromodomain (bromodomain 2 (1-473), bromodomain 3 (1-435) and bromodomain 4 (1-477)) Bacillus coli cells (in pET15b carrier) at N-end and express.Use 0.1mg/ml N,O-Diacetylmuramidase harmony facture from Bacillus coli cells, extract the bromodomain of this His-mark.Then by this bromodomain of affinity chromatography purifying, described affinity chromatography carries out on HisTRAP HP post, with linear 10-500mM imidazole gradient wash-out, more than 20 Cv.Completed by Superdex 200 preparation scale size-exclusion post and be further purified.The protein of purifying is stored in 20mM HEPES pH 7.5 and 100mM NaCl at-80 DEG C.
bromodomain 2 scheme: be dissolved in by all the components in the buffer compositions of 50mM HEPES pH 7.4,150mmNaCl and 0.5mM CHAPS, wherein bromodomain 2 ultimate density is 75nM, fluorescent ligand is 5nM.Use micro-skimmer this reaction mixture of 10 μ l to be added into containing in the test compounds of the various concentration of 100nl or the hole of DMSO medium (1% is final) of Greiner 384 hole Black low volume microwell plate, and at room temperature balance 60 minutes in dark.Fluorescence anisotropy (λ ex=485nm, λ EM=530nm is read in Envision; Dichroism-505nM).
bromodomain 3 scheme: be dissolved in by all the components in the damping fluid consisting of 50mM HEPES pH 7.4,150mm NaCl and 0.5mM CHAPS, wherein bromodomain 3 ultimate density is 75nM, fluorescent ligand is 5nM.Use micro-skimmer this reaction mixture of 10 μ l to be added into containing in the test compounds of the various concentration of 100nl or the hole of DMSO medium (1% is final) of Greiner 384 hole Black low volume microwell plate, and at room temperature balance 60 minutes in dark.Fluorescence anisotropy (λ ex=485nm, λ EM=530nm is read in Envision; Dichroism-505nM).
bromodomain 4 scheme: be dissolved in by all the components in the damping fluid consisting of 50mM HEPES pH 7.4,150mm NaCl and 0.5mM CHAPS, wherein bromodomain 4 ultimate density is 75nM, fluorescent ligand is 5nM.Use micro-skimmer this reaction mixture of 10 μ l to be added into containing in the test compounds of the various concentration of 100nl or the hole of DMSO medium (1% is final) of Greiner 384 hole Black low volume microwell plate, and at room temperature balance 60 minutes in dark.Fluorescence anisotropy (λ ex=485nm, λ EM=530nm is read in Envision; Dichroism-505nM).
In above-described each BRD2, BRD3 and BRD4 experiment, pIC >=6.0 of embodiment 1.
The whole blood that LPS stimulates measures the experiment of TNF alpha levels
Key inflammatory medium is caused to comprise the generation of TNF α by Toll-like receptor agonist such as bacteria lipopolysaccharide (LPS) activated monocyte.Extensively think that the physiopathology of this approach for a series of autoimmunization and inflammatory conditions is main.
Dilute compound to be tested to obtain a series of suitable concn, and 1ul is diluted stoste and be added in the hole of 96 orifice plates.After adding whole blood (130ul), by this plate in 37 degree of (5%CO 2) incubation 30 minutes, then add the 2.8ug/ml LPS (being diluted in (ultimate density=200ng/ml) in complete RPMI 1640) of 10ul, to obtain cumulative volume for the every hole of 140ul.Under 37 degree after further incubation 24 hours, 140ul PBS is added in each hole.Seal this plate, jolting 10 minutes, then centrifugal (2500rpmx10 minute).Remove 100ul supernatant liquor, even exist side by side-20 degree under store after measure TNF alpha levels by immunoassay (typically via MesoScale Discovery technology).Produced the dose response curve of each compound by these data, and calculate IC50 value.
The pIC50 > 6.0 of embodiment 1 is found in above-mentioned experiment.
These data show that the embodiment 1 of testing in above-mentioned experiment suppresses the generation of key inflammatory medium T NF α.This points out this compound to have strong anti-inflammatory power, and it probably changes into the clinical benefit of inflammatory conditions.
mouse endotoxin mass formed by blood stasis model in body
Intracellular toxin (bacteria lipopolysaccharide) generation giving animal high dosage comprises the profound shock syndrome of strong inflammatory responses, cardiovascular dysfunction, organ failure and finally death.This response mode and mankind's septicemia and septic shock (wherein health can life-threatening similarly to the response of a large amount of bacteriological infection) are closely similar.
In order to the formula of testing (I) compound and its pharmacy acceptable salt, given the 15mg/kg LPS of the group lethal quantity of eight Balb/c male mices by peritoneal injection.After 90 minutes, in animals iv, give medium (20% cyclodextrin 1% ethanol is in apirogen water) or compound (10mg/kg).The survival of monitoring animal 4 days.
The number of animals (repeatedly repeating the total of testing) of survival in 4 days
Medium 4/66 (6%)
Embodiment 1 24/56 (52%)
These data show that the embodiment 1 that intravenously gives to test in rear above-mentioned model significantly improves animal dis motility rate.This shows that formula (I) compound has the potentiality of effect of depth mankind inflammatory responses.
Whole open (the including but not limited to patent and patent application) of quoting in this specification sheets are herein incorporated with way of reference, just as each separately open shows to be herein incorporated with way of reference particularly and individually, all list in this as it.

Claims (11)

1. formula (I) compound, it is 2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide
Or its salt.
2. formula (I) compound, it is 2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide
Or its pharmacy acceptable salt.
3. formula (I) compound, it is 2-[(4S)-6-(4-chloro-phenyl-)-1-methyl-8-(methoxyl group)-4H-[1,2,4] triazolo [4,3-a] [Isosorbide-5-Nitrae] benzodiazepine -4-base]-N-ethyl acetamide
4. pharmaceutical composition, it comprises formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle as defined in claim 2.
5. pharmaceutical composition, it comprises formula (I) compound and one or more pharmaceutically acceptable carrier, thinner or vehicle as defined in claim 3.
6. medicinal composition product, it comprises formula (I) compound or its pharmacy acceptable salt and one or more other therapeutic activity agent as defined in claim 2.
7. formula (I) compound or its pharmacy acceptable salt are needing the purposes in the disease of bromodomain inhibitor or the medicine of illness for the preparation for the treatment of as defined in claim 2.
8. purposes as claimed in claim 7, wherein said disease or illness are chronic auto-immune and/or inflammatory conditions.
9. purposes as claimed in claim 7, wherein said disease or illness are cancer.
10. purposes as claimed in claim 9, wherein said cancer is blood cancer, lung cancer, mammary cancer, colorectal carcinoma, center line cancer, mesenchymal neoplasm, liver neoplasm, tumor of kidney and nervous system neoplasm.
11. purposes as claimed in claim 10, wherein said cancer is hematologic cancers is leukemia.
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